title: Identification of a candidate single-nucleotide polymorphism related to chemotherapeutic response through a combination of knowledge-based algorithm and hypothesis-free genomic data.
abstract: Inter-individual variations in drug responses among patients are known to cause serious problems in medicine. Genome-wide association study (GWAS) is powerful for examining single-nucleotide polymorphisms (SNPs) and their relationships with drug response variations. However, no significant SNP has been identified using GWAS due to multiple testing problems. Therefore, we propose a combination method consisting of knowledge-based algorithm, two stages of screening, and permutation test for identifying SNPs in the present study. We applied this method to a genome-wide pharmacogenomics study for which 109,365 SNPs had been genotyped using Illumina Human-1 BeadChip for 119 gastric cancer patients treated with fluoropyrimidine. We identified rs2293347 in epidermal growth factor receptor (EGFR) is as a candidate SNP related to chemotherapeutic response. The p value for the rs2293347 was 2.19 × 10(-5) for Fisher's exact test, and the p value was 0.00360 for the permutation test (multiple testing problems are corrected). Additionally, rs2293347 was clearly superior to clinical parameters and showed a sensitivity value of 55.0% and specificity value of 94.4% in the evaluation by using multiple regression models. Recent studies have shown that combination chemotherapy of fluoropyrimidine and EGFR-targeting agents is effective for gastric cancer patients highly expressing EGFR. These results suggest that rs2293347 is a potential predictive factor for selecting chemotherapies, such as fluoropyrimidine alone or combination chemotherapies.
authors.affiliation: Graduate School of Horticulture, Chiba University, 648 Matsudo, Matsudo, Chiba 271-8510, Japan; Plant Biology Research Center, Chubu University, Matsumoto-cho 1200, Kasugai, Aichi 487-8501, Japan; Division of Genetics, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan. Electronic address: hiro.takahashi@chiba-u.jp.
authors.forename: Hiro
authors.initials: H
authors.lastname: Takahashi
authors.forename: Nahoko
authors.initials: N
authors.lastname: Kaniwa
authors.forename: Yoshiro
authors.initials: Y
authors.lastname: Saito
authors.forename: Kimie
authors.initials: K
authors.lastname: Sai
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Hamaguchi
authors.forename: Kuniaki
authors.initials: K
authors.lastname: Shirao
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Shimada
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Matsumura
authors.forename: Atsushi
authors.initials: A
authors.lastname: Ohtsu
authors.forename: Takayuki
authors.initials: T
authors.lastname: Yoshino
authors.forename: Anna
authors.initials: A
authors.lastname: Takahashi
authors.forename: Yoko
authors.initials: Y
authors.lastname: Odaka
authors.forename: Misuzu
authors.initials: M
authors.lastname: Okuyama
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Sawada
authors.forename: Hiromi
authors.initials: H
authors.lastname: Sakamoto
authors.forename: Teruhiko
authors.initials: T
authors.lastname: Yoshida
mesh_terms: D000465:Algorithms; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000235:genetics; D019295:Computational Biology; D066246:ErbB Receptors / Q000235:genetics; D005260:Female; D005472:Fluorouracil / Q000494:pharmacology; D055106:Genome-Wide Association Study; D023281:Genomics; D006801:Humans; D008297:Male; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide; D012044:Regression Analysis; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000235:genetics*
chemical_list: D000964:Antimetabolites, Antineoplastic; D066246:ErbB Receptors; D005472:Fluorouracil
keywords: Bioinformatics; Fluoropyrimidine; Gastric cancer; Genome-wide association study; Single-nucleotide polymorphisms